Novel use of selective pde5 inhibitors

ABSTRACT

The invention relates to the novel use of PDE5 inhibitors for the treatment of patients in which a mismatch is present.

TECHNICAL FIELD

The invention relates to novel use of selective PDE5 inhibitors in thetreatment of pulmonary disorders.

PRIOR ART

In the healthy lung both at rest and during exercise there are alwaysareas of good and poor or absolutely no ventilation existingsimultaneously side by side (ventilation inhomogeneity). An as yetunknown mechanism ensures that there is ittle or no perfusion of thecapillaries adjacent to alveoli with little or no ventilation. Thisoccurs in order to minimize inefficient perfusion of areas of the lungwhich are not involved in gas exchange.

Necessary for efficient gas exchange in the lung is a dynamic adaptationof the perfusion conditions to the continual changes in regionalventilation. This coupling is referred to as matching and is determinedqualitatively and quantitatively as the V/Q ratio(ventilation/perfusion) by means of the multiple inert gas eliminationtechnique (MIGET).

During bodily exercise, the distribution of ventilation changes(recruitment of new alveoli) and there is increased perfusion of therelevant capillary bed. Conversely, when there is less ventilation dueto physiological or pathological processes (airway obstruction), thecapillary flow are reduced through vasoconstriction. This process isreferred to as “hypoxic vasoconstriction” (Euler-Liljestrand mechanism).

When this adaptation mechanism is impaired (“mismatch”), there may,despite adequate ventilation and normal perfusion of the lungs, be amore or less pronounced collapse of the gas exchange function, which canbe compensated only inadequately despite a further increase inventilation or perfusion. Under these conditions there are regions whichare not ventilated but are well perfused (shunting) and those which arewell ventilated but not perfused (dead space ventilation), and allintermediate states characterized by deviations from the normal value ofV/Q=1. These are, on the one hand, low-V/Q areas (hyperperfusion withlittle ventilation), and on the other hand high-V/Q areas (hypoperfusionwith hyperventilation). The consequence of this mismatch are hypoxaemia(deterioration in gas exchange with decrease in the oxygen content ofthe patient's blood), wasted perfusion (uneconomical perfusion ofunventilated areas) and wasted ventilation (uneconomical ventilation ofpoorly perfused areas). This leads to a limitation in the patient'sperformance due to a deficient oxygen supply to the muscles incombination with a “squandering” of cardiorespiratory reserves. Theclinical symptoms are a limitation on performance and exercise-dependentor permanent dyspnoea.

In patients with inflammatory and degenerative lung disorders such as,for example, chronic obstructive bronchitis (COPD), bronchial asthma,pulmonary fibroses, emphysema, interstitial pulmonary disorders andpneumonias there is observed to be partial or global respiratoryfailure. The cause is inadequate adaptation of the intrapulmonaryperfusion conditions to the inhomogeneous pattern of the distribution ofventilation. The mismatch derives from the effect of vasoactive(inflammatory) mediators which prevail over the physiological adaptationmechanism. This effect is particularly evident during exercise and whenthe oxygen demand is increased and it is manifested by dyspnoea(hypoxia) and limitation of performance.

Administration of vasodilators (endothelin antagonists, angiotensin IIantagonists, prostacyclin [systemically administered, orally orintravenously], calcium channel blockers) may considerably exacerbatethe impairment of the gas exchange function, caused by nonselectivevasodilation, especially in the poorly ventilated areas of the lungs,resulting in an increase in mismatch and shunting.

Administration of a vasodilator (especially nitric oxide, NO) byinhalation has a theoretically preferred effect only in thewell-ventilated areas of the lungs. However, this requires an efficientinhalation technique which is troublesome for the patient. Additionalfactors are the systemic effects on absorption through the alveolarepithelium (especially with substances having a long duration of action)and the possible irritation of the bronchial system.

Bronchodilators are intended to reduce airway obstruction which ispresent. However, in previously damaged lungs they may in fact aggravatefurther the mismatch, which is the main cause of the reducedperformance, through increasing the ventilation in so-called high-V/Qareas and by unwanted systemically vasodilatation (increase in perfusionin low-V/Q areas).

A whole series of PDE5 inhibiting substances (PDE=phosphodiesterase) areknown from the prior art and are described as potent and effectivesubstances for the treatment of erectile dysfunction. In addition, EP1097911 discloses that PDE5-inhibiting substances can be employed forthe treatment of pulmonary hypertension and Prasad et al. [Prasad et al.(2000) New England Journal of Medicine 343: 1342] postulate a beneficialrole of Sildenafil in primary pulmonary hypertension. EP 758653discloses that PDE inhibitors are useful for treating bronchitis,chronic asthma, and hypertension.

Grimminger et al. [Grimminger F et al. (2000) Zeitschrift farKardiologie 89:477] disclose that there are two pharmacologicalapproaches to reduce vascular resistance in patients suffering fromchronic pulmonary hypertension: (1) Use of anti-agulatory andfibrinolytic drugs and (2) use of vasodilators with anti-inflammatoryand anti-proliferative potency such as prostanoids. Grimminger at al.disclose that the inhalative route of administration is superior becauseof the pulmonary selectivity and that the decrease in pulmonary-vascularresistance is paralleled by both optimized ventilation-perfusionmachting as well as subsequently improved gas exchange. Grimminger etal. also disclose the use of inhaled nitric oxide and aerosolizedprostacyclin in ventilated patients with septic lung failure.

Barnes et al. [Barnes P J et al. (1995) Eur. Resp. J. 8:457] describethe involvement of PDE5 in the degradation of cGMP in smooth musclecells of the airways and vessels.

Kleinsasser A. et al. [Kleinsasser A. et al. (2001) American Journal ofRespiratory and Critical Care Medicine 163:339] describes thedemonstration that sildenafil modulates the haemodynamics and pulmonarygas exchange in a pig model. However, the skilled person is aware thatthere are differences between the human and porcine species in relationto pulmonary haemodynamics and gas exchange [Mazzone R W et al. (1981)J.Appl.Physiol 51:739; Woolcock A J et al. (1971) J. Appl. Physiol30:99; Hogg W et al. (1972) J. Appl. Physiol 33:568; Kurlyama T (1981)J. Appl. Physiol 51:1251; Hedenstiema G et al. (2000) Respir. Physiol.120:139; Bastacky J et al. (1992) J. Appl. Physiol 73:88]. Thus, pigslack so-called collateral ventilation. In addition, in pigs there is thephenomenon of pulmonary vascular hyperagility (compared with humans). Itis thus clear to the skilled person that results in the pig model cannotbe applied directly to humans.

DESCRIPTION OF THE INVENTION

The object of the present invention is thus to provide a substancewhich, on oral, intravenous or else inhalational administration, leadson the one hand to the preferred dilatation of vessels in the pulmonarycirculation (pulmonary selectivity) and, at the same time, to aredistribution of the blood flow within the lung in favour of thewell-ventilated areas

It has now been found, surprisingly, that selective PDE5 inhibitors aresuitable for the treatment of patients having the abovementionedmismatch. Administration of selective PDE5 inhibitors leads todilatation of vessels in the pulmonary circulation and, at the sametime, to a redistribution of the blood flow within the lung in favour ofthe well-ventilated areas. This principle, referred to hereinafter asrematching, leads to an improvement in the gas exchange function both atrest and during physical exercise.

Contrary to the skilled person's expectation, that the vasodilatingeffect achieved with a PDE5 inhibitor has neither pulmonary orintrapulmonary selectivity, it emerges that there was not only adeterioration but in most cases a significant improvement ofpre-existent gas exchange impairments in the treated patients. SelectivePDE5 inhibitors are thus suitable as rematching medicament. Thisimprovement in the oxygen supply is not brought about by the well-knowngeneral (pulmonary and systemic) vasorelaxation which is typical of PDE5inhibitors. On the contrary, the improvement in gas exchange derivesfrom PDE5 inhibitors bringing about or enhancing a lung-selective andintrapulmonary-selective vasodilatation in the well-ventilated regions.It is thus possible in patients with a pronounced gas exchangeimpairment to improve markedly a restricted oxygen supply throughadministration of selective PDE5-inhibiting substances. In addition, thefunctional capacity of these patients is significantly improved througha reduction in wasted ventilation and wasted perfusion.

The invention thus relates to the use of PDE5 inhibitors for thetreatment of partial and global respiratory failure.

According to the invention, selective PDE5 inhibitors and PDE5inhibitors are regarded as synonymous.

In connection with this invention, use of PDE5 inhibitors refer to theuse of at least one PDE5 inhibitor.

According to this invention, respiratory failure relates to animpairment of oxygen uptake or carbon dioxide release in the lung.Partial respiratory failure according to the invention relates to a fallin the O₂ partial pressure in the blood as a manifestation of theaforementioned impairment of oxygen uptake or carbon dioxide release.According to this invention, global respiratory failure relates to afall in the O₂ partial pressure in the blood and a rise in the CO₂partial pressure in the blood as a manifestation of the aforementionedimpairment of oxygen uptake or carbon dioxide release.

The invention further relates to the use of PDE5 inhibitors forproducing medicaments for the treatment of partial and globalrespiratory failure.

The invention further relates to the use of PDE5 inhibitors forproducing medicaments for the treatment of respiratory failure inpatients who have a mismatch of pulmonary ventilation and pulmonaryperfusion.

According to this invention, a patient is a human. Preferably, a patientrefers to a human in need of medical care or treatment.

The mechanism of the intrapulmonary-selective effect of selective PDE5inhibitors is based on the inhomogeneity of substrate distribution(cGMP, cyclic guanosine monophosphate) caused by vasodilatation duringnormal ventilation.

According to this invention, vasodilatation during normal ventilationrelates to a local increase in activity of NO synthase inwell-ventilated lung areas due to alveolar distension. This results inan increased cGMP synthesis (activation of guanylate cyclase by NO)compared with poorly ventilated lung areas.

It can be stated on the basis of the findings which have been obtainedthat selective PDE5 inhibitors are able to enhance, in the sense ofphysiological adaptation of ventilation and perfusion, the necessaryvasodilatations specifically in the well-ventilated regions in that theyaccentuate the physiological inhomogeneity of cGMP distribution in thelung and thus promote rematching. Gas exchange is intensified and theoxygen supply is improved by this mechanism. Selective PDE5 inhibitorsthus make selective relaxation of pulmonary vessels possible at the siteof adequate ventilation.

A mismatch of pulmonary ventilation and pulmonary perfusion—up to theextremes of dead space ventilation and the shunting—may be caused byvarious inflammatory and degenerative lung disorders.

This mismatch may be present even at rest but may also appear only underconditions of increased ventilation and perfusion (meaning duringexercise) (stress failure of the mismatch).

The invention thus relates to the use of selective PDE5 inhibitors forproducing medicaments for the treatment of respiratory failure inpatients with an exercise-related mismatch.

The phenomenon of exercise-induced ventilation/perfusion inhomogeneityoccurs not only when there are underlying lung disorders, but alsoduring normal aging processes (aging). However, in contrast toinflammatory and degenerative lung disorders, the main feature ofage-related mismatch is an increasing rigidity of the pulmonary vessels,resulting in loss of the adaptation-optimizing physiological reflexes(hypoxic vasoconstriction). The mode of action of selective PDE5inhibitors in these cases derives preferentially from the regionallyselective vasodilating effect of the substances and the augmentation ofthe physiological residual signal (endogenous NO/prostacycline).

The invention further relates to the use of selective PDE5 inhibitorsfor producing medicaments for the treatment of respiratory failure inpatients with an age-related mismatch.

The invention further relates to the use of selective PDE5 inhibitorsfor producing medicaments for the treatment of respiratory failure inpatients with a pathologically caused mismatch.

Patients with a pathologically caused mismatch are patients with adisorder selected from the group consisting of orthopnoea, sleep apnoeaand COPD (chronic obstructive pulmonary disease).

The use of selective PDE5-inhibiting substances is suitable specificallyin patients with elevated low-V/Q perfusion (V/Q<0.1) to makephysiological adaptation (rematching) of pulmonary ventilation andpulmonary perfusion possible through selective vasodilatation at thesite of adequate ventilation. According to this invention, an elevatedlow-V/Q perfusion relates to areas of the lung in which ventilation islow but perfusion is good. A V/Q ratio can be determined in patientswith an elevated low-V/Q perfusion through gas exchange measurements bymeans of MIGET.

The invention further relates to the use of selective PDE5 inhibitorsfor producing medicaments for the treatment of respiratory failure inpatients with a V/Q of <0.1.

The invention additionally relates to the use of selective PDE5inhibitors in the production of medicaments for the treatment of COPDpatients with a predominating bronchitic component (0.001<V/Q<0.1).

COPD patients with a predominanting bronchitic component (called “bluebloaters”) are distinguished by the presence of low-V/Q areas. PDE5inhibitors contribute to rematching in this subgroup of patients throughthe predominant vasodilatation in the remaining ventilated areas of thelung.

The invention further relates to the use of selective PDE5 inhibitors inthe production of medicaments for the treatment of COPD patients with anemphysematous component. In particular, it relates to the use ofselective PDE5 inhibitors in the production of medicaments for thetreatment of COPD patients with an emphysematous component of V/Q>10.More particularly preferred, it relates to the use of selective PDE5inhibitors in the production of medicaments for the treatment of COPDpatients with a predominating emphysematous component.

COPD patients with a predominating emphysematous component (called “pinkpuffers”) are distinguished by the presence of high-V/Q areas andincreased dead-space ventilation as the cause of their mismatch. PDE5inhibitors can contribute to rematching in these patients because of anenhancement of perfusion in the hyperventilated areas (normalization ofthe V/Q ratio).

The invention additionally relates to the use of selective PDE5inhibitors in the production of medicaments for the treatment ofpatients with orthopnoea. Preference is given to those patientssuffering from posture-dependent impairments of gas exchange(orthopnoea) with nocturnal desaturation phases.

In a particular group of patients with manifest or latent respiratoryfailure there is a deterioration in gas exchange on passing from thevertical to the horizontal position (supine position). The change inposition results in a redistribution of the ventilation distribution andalso of the perfusion distribution, which are only poorly matched inthese patients. The limited adaptation capacity means that the matchingand correspondingly the O₂ saturation is reduced. This phenomenon ischaracterized clinically as orthopnoea. The patient develops criticalphases of hypoxia, especially during periods of sleep, with the dange ofunnoticed undersupply of oxygen, especially to the brain and myocardium.Selective PDE5 inhibitors are able, owing to the rematching effect, toincrease the O₂ saturation in these patients and to reduce the risk ofsecondary organ damage.

The invention further relates to the use of selective PDE5 inhibitors inthe production of medicaments for the treatment of patients sufferingfrom sleep apnoea.

According to this invention, sleep apnoea is a nocturnal disturbance ofrespiratory regulation in which arterial hypoxia develops. Thesepatients differ from other patients in that, owing to failure of thecentral respiratory drive or owing to anatomically caused peripheralobstruction (tongue versus the upper airways), alveolar ventilation isrestricted as alveolar hypoxia is induced. The hypoxic vasoconstrictioninduced thereby with a subsequent rise in the pulmonary vascularresistance and severe stress on the right heart leads to damage to themyocardium (cor pulmonale) and to the blood vessels (essentialhypertension). Administration of conventional vasodilators can certainlydilate the pulmonary vessels and thus reduce the stress on the rightheart, but at the cost of a further deterioration in the alreadyimpaired gas exchange function through aggravation of the mismatch.Administration of selective PDE5 inhibitors thus makes it possiblesimultaneously to reduce the pulmonary vascular resistance and toprevent or reduce the mismatch.

The invention further relates to the use of selective PDE5-inhibitingsubstances in the production of medicaments for the treatment of atherapy-indiced mismatch.

In the treatment of patients with respiratory failure with β2 agonists,theophylline or systemic vasodilators (endothelin antagonists, Cachannel blockers, ACE inhibitors, ATII antagonists, β blockers) there isenhancement of a mismatch which is present. Although the vascularresistance in the lung is reduced on treatment with these medicines,simultaneously the O₂ saturation is reduced. This loss of O₂ saturationincreasingly reduces the functional capacity of a patient which isalready limited. Consequently, a latent or manifest respiratory failuremay be induced in these patients through intake of nonselectivevasodilators which is necessary to treat other disorders(therapy-induced mismatch). Selective PDE5 inhibitors are suitable fortreating this type of respiratory failure.

Preference is given to uses of selective of PDE5 inhibitors for thetreatment of a therapy-induced mismatch on administration ofnonselectively vasodilating medicaments, especially nonselectivelyvasodilating antiobstructive agents.

This invention further relates to the use of selective PDE5 inhibitorsfor producing medicaments for the treatment of muscular dysfunctioncaused by perfusion/demand mismatch.

In skeletal muscles (including the respiratory muscle) these is astress-control adaptation of perfusion to the regional energy demand.Regulation of this “perfusion/demand matching” takes place in analogy tothe lung through local release of endogenous vasodilators (especiallyNO/cGMP). The demand-oriented perfusion is in favour of the stressedmuscle groups (muscular selectivity), and within the muscle groups infavour of the specifically stressed fibre types (intramuscularselectivity). The type of stress, duration of stress and level of stressthus determine under physiological conditions the specific perfusionprofiles in each case. Various inflammatory disorders (COPD,interstitial lung disorders, infections, vasculitides, degenerativevascular disorders, metabolic disorders), but also the use ofnonselective vasoactive medicines for the treatment of theabovementioned disorders, may lead to a perfusion/demand mismatch. Theconsequence is wasted perfusion of unstressed muscle groups to thedetriment of perfusion of stressed muscle groups, with the result of alimitation on muscular performance. PDE5 inhibitors are able to augmentthe physiological NO/cGMP distribution pattern and thus achieve muscularrematching.

This invention further relates to a medicament preparation comprising atleast one selective PDE5 inhibitor and at least one nonselectivelyvasodilating antiobstructive agent. Such a combination is preferred forthe treatment of partial and global respiratory failure. Such acombination is particularly preferred for the treatment of disordersselected from the group consisting of COPD, bronchial asthma, latentpulmonary hypertension associated with underlying lung disorder,emphysema, combined ventilation impairments, chronic left heart failurewith pulmonary congestion.

Antiobstructive agents which may induce, for example, endothelinantagonists, Ca channel blockers, ACE inhibitors, ATII antagonists and βblockers. Examples of antiobstructive agents which may be mentioned areendothelin antagonists such as ATRASENTAN, BMS-193884, BOSENTAN,BSF-302146, DARUSENTAN, EDONENTAN, J-104132, SB-209670, SITAXENTAN,TBC-3711, TEZOSENTAN and YM-598, Ca channel blockers such as AMLODIPINE,ARANIDIPINE, BARNIDIPINE, BENCYCLANE, BENIDIPINE, BEPRIDIL, BUFLOMEDIL,CAROVERINE, CILNIDIPINE, CINNARIZINE, DILTIAZEM, DROPRENILAMINE,EFONIDIPINE, FASUDIL, FELODIPINE, FENDILINE, FLUNARIZINE, GALLOPAMIL,ISRADIPINE, LACIDIPINE, LERCANIDIPINE, LIDOFLAZINE, LOMERIZINE,MANIDIPINE, NICARDIPINE, NIFEDIPINE, NILVADIPINE, NIMODIPINE,NISOLDIPINE, NITRENDIPINE, PERHEXILINE, TERODILINE and VERAPAMIL, ACEinhibitors such as ALACEPRIL, BENAZEPRIL, CAPTOPRIL, CERONAPRIL,CILAZAPRIL, DELAPRIL, ENALAPRIL, ENALAPRILAT, FOSINOPRIL, IMIDAPRIL,LISINOPRIL, MOEXIPRIL, PERINDOPRIL, QUINAPRIL, RAMIPRIL, RENTIAPRIL,SPIRAPRIL, TEMOCAPRIL and TRANDOLAPRIL, ATII antagonists such asABITESARTAN, CL-329167, DA-727, ELISARTAN, EMD-66397, FK-739, HR-720,ICI-D-8731, IRBESARTAN, KRH-594, LR-B/057, MILFASARTAN, OLMESARTANMEDOXOMIL, POMISARTAN, PRATOSARTAN, RIPISARTAN, SAPRISARTAN, TAK-536,TASOSARTAN, TELMISARTAN, U-96849, VALSARTAN and ZOLASARTAN, and βblockers such as CEBUTOLOL, ALPRENOLOL, AROTINOLOL, ATENOLOL, BEFUNOLOL,BETAXOLOL, BEVANTOLOL, BISOPROLOL, BOPINDOLOL, BUNITROLOL, BUPRANOLOL,CARAZOLOL, CARTEOLOL, CARVEDILOL, CELIPROLOL, DILEVALOL, ESMOLOL,LABETALOL, LEVOBUNOLOL, MEPINDOLOL, METIPRANOLOL, METOPROLOL, MOPROLOL,NADOLOL, NEBIVOLOL, NIPRADILOL, OXPRENOLOL, PENBUTOLOL, PINDOLOL,PRACTOLOL, PROPRANOLOL, SOTALOL, TALINOLOL, TERTATOLOL, TILISOLOL,TIMOLOL, TOLIPROLOL and XAMOTEROL.

Nonselectively vasodilating antiobstructive agents are used inmedicaments for the treatment of obstructive ventilation impairment.Administration of such antiobstructive agents may considerablyexacerbate the disturbance of gas exchange function, caused by anonselectve vasodilatation—especially in the poorly ventilated lungareas—which may lead to an increase in mismatch and shunting. PDE5inhibitors are able to show their selective effect also in combinationwith nonselectively vasodilating antiobstructive agents and, throughtheir selective effect, compensate the mismatch caused by thenonselectively vasodilating antiobstructive agents. Nonselectivelyvasodilating antiobstructive agents and selective PDE5 inhibitors can beadministered in a fixed combination. It is likewise possible toadminister nonselectively vasodilating antiobstructive agents andselective PDE5 inhibitors as free combination—singly—in which caseadministration can take place in immediate succession or at a relativelylarge time interval. According to this invention, a relatively largetime interval relates to a time interval of up to a maximum of 24 hours.

Substances which may be included among PDE5 inhibitors and selectivePDE5 inhibitors for example are those described and claimed in thefollowing patent applications and patents: WO 9626940, WO 9632379, EP0985671, WO 9806722, WO 0012504, EP 0667345, EP 0579496, WO 9964004, WO9605176, WO 9307124, WO 9900373, WO 9519978, WO 9419351, WO 9119717, EP0463756, EP 0293063, WO 0012503, WO9838168, WO 9924433, DE 3142982 andU.S. Pat. No. 5,294,612.

Compounds which may be mentioned as examples of PDE5 inhibitors andselective PDE5 inhibitors are3-ethyl-8-[2-(4-morpholinylmethyl)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione,1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide,9-bromo-2-(3-hydroxypropoxy)-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-[k]-carbazol-4-one,4-(1,3-benzodioxol-5-ylmethylamino)-2-(1-imidazolyl)-6-methylthieno[2,3-pyrimidine,6-(2-isopropyl-4,5,6,7-terahydropyrazolo[1,5-a]pyridin-3-yl)-5-methyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one,5-(4-methylbenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-pyridin-4-ylmethyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(4-bromobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-benzyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(3,4-dimethoxybenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one,5-(3,4-dichlorobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-biphenyl-4-ylmethyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(4-aminobenzyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(hydroxyphenylmethyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one,5-benzo[1,3]dioxol-5-ylmethyl-3-[1-methyl-4-phenylbutyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,N-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo-[4,5-d]pyrimidin-5-ylmethyl]phenylacetamide,5-benzoyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]-pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-[4-(morpholine-4-sulphinyl)benzyl]-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-[3-(morpholine-4-sulphonyl)benzyl]-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one,N-methyl-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]-benzenesulphonamide,N-(2-dimethylaminoethyl)-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonamide,N-(2-hydroxyethyl)-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonamide,ethyl1-[3-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonyl]piperidinecarboxylate,3(1-methyl-4-phenylbutyl)-5-[4-(4-methylpiperazin-1-sulphonyl)benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5d]pyrimidin-7-one,5-benzo[1,3]dioxol-5-ylmethyl-3-[1-ethyl-heptyl]-3,6-dihydro-[1,2,3]-triazolo[4,5-d]pyrimidin-7-one,3-[1-(1-hydroxyethyl)-4-phenylbutyl]-5-[4-(morpholine-4-sulphonyl)benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-[6-fluoro-1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol,1-benzyl-6-fluoro-3-[5-(hydroxymethyl)furan-2-yl]-1H-indazole,2-(1H-imidazol-1-yl)-6-methoxy-4-(2-methoxyethylamino)quinazoline,1-[[3-dihydro-8-oxo-1H-imidazo[4,5-g]quinazolin-6-yl)-4-propoxyphenyl]sulphonyl]-4-methylpiperazine,4-(3-chloro-4-methoxybenzylamino)-1-(4-hydroxypiperidin-1-yl)phthalazine-6-carbonitrile,1-[6-chloro-4-(3,4-methylendioxybenzylamino)quinazolin-2-yl]piperidin-4-carboxylicacid, (6R, 12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octa-hydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione(tadalafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione,4-ethoxy-2-phenylcycloheptylimidazole, (6-bromo-3-methoxymethylimidazo[1,2-a]pyrazin-8-yl)methylamine,8-[(phenylmethyl)thio]4-(1-morpholinyl)-2-(1-piperazinyl)pyrimidino[4,5-d]pyrimidine,(+)-cis-5-methyl-2-[4-(trifluoromethyl)benzyl]-3,4,5,6a,7,8,9-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one,cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5imidazo[2,1-b]purin-4-one,5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(slidenafil),1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine,2-(2-propoxyphenyl)purin-6(1H)-one,2-(2-propoxyphenyl)-1,7-dihydro-5H-purin-6-one, methyl2-(2-methylpyridin-4-ylmethyl)-1-oxo-8-(2-pyrimidinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-[2,7]naphthyridin-3-carboxylate,methyl 2-(4-aminophenyl)-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydroisoquinoline-3-carboxylate,2-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)phenyl]-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(vardenafil),3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2-(1H)-quinolinone(vesnarinone), 1-cyclopentyl-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one,1-cyclopentyl-6-(3-ethoxy-4-pyridinyl)-3-ethyl-1,7-dihydro-4H-pyrazolo[3,4-d]-pyrimidin-4-one,6-o-propoxyphenyl-8-azapurin-6-one,3,6-dihydro-5-(o-propoxyphenyl)-7H-v-triazolo[4,5-d]pyrimidin-7-one and4-methyl-5-(4-pyridinyl)thiazole-2-carboxamide and the pharmacologicallyacceptable salts of these compounds.

PDE5 inhibitors and selective PDE5 inhibitors which are particularlypreferred are selected from the group consisting of tadalafil,sildenafil, vardenafil and vesnarinone and the pharmacologicallyacceptable salts of these compounds.

Suitable salts are—depending on the substitution and depending on thebasic structure—in particular all acid addition salts or else salts withbases. Particular mention may be made of the pharmacologicallyacceptable salts of the inorganic and organic acids normally used inpharmaceutical technology. Suitable as such are water-soluble andwater-insoluble acid addition salts with acids such as, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonicacid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in the preparation of salts—depending on whether the acidis monobasic or polybasic and depending on which salt is desired—in theequimolar ratio of amounts or one differing therefrom. Particularmention should also be made of the pharmacologically acceptable salts ofthe inorganic and organic bases normally used in pharmaceuticaltechnology. Suitable as such are water-soluble and water-insoluble saltswith bases such as, for example, sodium hydroxide solution, potassiumhydroxide solution or ammonia.

In the use according to the invention of PDE5 inhibitors or selectivePDE5 inhibitors for producing the aforementioned medicaments and in thepharmaceutical preparations according to the invention, the PDE5inhibitors or selective PDE5 inhibitors (=the active ingredients) areprocessed with suitable pharmaceutical excipients or carriers totablets, coated tablets, capsules, suppositories, plasters (e.g. astransdermal therapeutic system=TTS), emulsions, suspensions orsolutions, with the active ingredient content advantageously beingbetween 0.1 and 95%, and it being possible by appropriate choice of theexcipients and carriers to obtain a pharmaceutical dosage form (e.g. aslow-release form or an enteric form) which is exactly adapted to theactive ingredient and/or to the desired onset of action.

Excipients and carriers suitable for the desired pharmaceuticalformulations are familiar to the skilled person on the basis of hisexpert knowledge. Besides solvents, gel formers, suppository bases,tablet excipients and other active ingredient carriers it is possible touse, for example, antioxidants, dispersants, emulsifiers, antifoams,masking flavours, preservatives, solubilizers, colours or, inparticular, permeation promoters and complexing agents (e.g.cyclodextrins).

The active ingredient can be administered orally, by inhalation,percutaneously, transdermally or intravenously.

It has generally proved advantageous in human medicine to administer theactive ingredient in the case of oral administration in a daily dose ofabout 0.02 to about 4 mg, in particular 0.1 to 2 mg per kg of bodyweight, where appropriate in the form of a plurality of, preferably 1 to3, individual doses to achieve the desired result, with graduallyincreasing and decreasing dosage possibly being advantageous. Onparenteral treatment it is possible to use similar or (especially onintravenous administration of the active ingredient) usually lowerdosages.

The skilled person is aware that the optimal dose of an activeingredient may vary depending on the body weight, the age and thegeneral condition of the patient, and on his response to the activeingredient.

Every skilled person is easily able to establish on the basis of hisexpert knowledge the optimal dosage and mode of administration of theactive ingredient necessary in each case.

The invention further relates to a commercial product consisting of aconventional secondary packaging, of a primary packaging containing themedicament (for example an ampoule or a blister) and, if desired, apackage insert, where the medicament is used for the treatment ofpartial and global respiratory failure, the suitability of themedicament for the treatment of partial and global respiratory failureis indicated on the secondary packaging and/or on the package insert ofthe commercial product, and the medicament comprises a PDE5 inhibitor.The secondary packaging, the medicament-containing primary packaging andthe package insert otherwise correspond to that which the skilled personwould regard as standard for medicaments of this type.

The invention further relates to a ready-to-use medicament comprising aPDE5 inhibitor and an indication that this medicament can be employedfor the treatment of partial and global respiratory failure.

The invention further relates to a method of treating partial and globalrespiratory failure in a human in need thereof comprising the step ofadministering to said human a therapeutically effective amount of a PDE5inhibitor.

According to this invention, a therapeutically effective amount of aPDE5 inhibitor refers to the pharmacologically tolerable amount of thePDE5 inhibitor sufficient, either as a single dose or as a result ofmultiple doses, to decrease the mismatch of pulmonary ventilation andpulmonary perfusion, or to reduce wasted perfusion and wastedventilation.

The invention further relates to a method of treating respiratoryfailure in a human showing a mismatch of pulmonary ventilation andpulmonary perfusion comprising the steps of administration to said humanin need a therapeutically effective amount of a selective PDE5inhibitor. In particular, the human in need having a mismatch of V/Q<0.1are preferred.

The invention further relates to a method of treating respiratoryfailure in a human showing an exercise-dependent mismatch of pulmonaryventilation and pulmonary perfusion comprising the steps ofadministration to said human in need a therapeutically effective amountof a selective PDE5 inhibitor.

The invention further relates to a method of treating respiratoryfailure in a human showing an age-related mismatch of pulmonaryventilation and pulmonary perfusion comprising the steps ofadministration to said human in need a therapeutically effective amountof a selective PDE5 inhibitor. In particular, the human in need having amismatch of V/Q<0.1 are preferred.

The invention further relates to a method of treating respiratoryfailure in a human showing pathologically caused mismatch of pulmonaryventilation and pulmonary perfusion comprising the steps ofadministration to said human in need a therapeutically effective amountof a selective PDE5 inhibitor. In particular, the human in need having amismatch of V/Q<0.1 are preferred.

The invention further relates to a method of treating respiratoryfailure in a COPD patient with a predominant bronchitis componentshowing a mismatch of pulmonary ventilation and pulmonary perfusioncomprising the steps of administration to said human in need atherapeutically effective amount of a selective PDE5 inhibitor. Inparticular, a COPD patient having a mismatch of V/Q<0.1 are preferred.

The invention further relates to a method of treating respiratoryfailure in a COPD patent with an emphysematous component showing amismatch of pulmonary ventilation and pulmonary perfusion comprising thesteps of administration to said human in need a therapeuticallyeffective amount of a selective PDE5 inhibitor. In particular, a COPDpatient having a mismatch of V/Q>10 is preferred.

The invention further relates to a method of treating orthopnoea in ahuman showing a mismatch of pulmonary ventilation and pulmonaryperfusion comprising the step of administering to said human atherapeutically effective amount of a PDE5 inhibitor.

The invention further relates to a method of treating sleep apnoea in ahuman showing a mismatch of pulmonary ventilation and pulmonaryperfusion comprising the step of administering to said human atherapeutically effective amount of a PDE5 inhibitor.

The invention further relates to a method of treating respiratoryfailure in a human showing a therapy-induced mismatch of pulmonaryventilation and pulmonary perfusion comprising the steps ofadministration to said human in need a therapeutically effective amountof a selective PDE5 inhibitor.

The invention further relates to a method of treating respiratoryfailure in a human showing a mismatch of pulmonary ventilation andpulmonary perfusion caused by administration of nonselectivelyvasodilating medicaments, the method comprises the steps ofadministration to said human in need a therapeutically effective amountof a selective PDE5 inhibitor. In particular, the method is preferred,wherein the nonselectively vasodilating medicament is a nonselectivelyvasodilating antiobstructive agent. The method is particularlypreferred, wherein the nonselectively vasodilating antiobstructive agentis selected from the group consisting of endothelin antagonist, Cachannel blocker, ACE inhibitor, ATII antagonist and β blocker.

The invention further relates to a method of treating musculardysfunction in a human showing a perfusion/demand mismatch comprisingthe step of administering to said human a therapeutically effectiveamount of a PDE5 inhibitor.

Further advantages and embodiments of the invention are described belowand are evident from the examples and the appended drawings.

DESCRIPTION OF THE FIGURES

FIG. 1: Result of determination of shunting with the aid of the model ofbleomycin-induced pulmonary fibrosis in rabbits. The measurements by theinert gas exchange method (MIGET) [Wagner et al., J Appl Physiol.1974;36:588-99] reveal that the shunting was increased by 15% in thismodel, compared with the untreated control. Systemically administeredPGI [6 ng/kg body weight/min] (PGI, prostacyclin) increased the shuntingto about 30%. Exogenous inhaled NO [20 parts per million (ppm)] bycontrast reduced the shunting to 9%. Shunting was reduced to 6% by oraladministration of the PDE5 inhibitor sidenafil [1 mg/kg body weight].

FIG. 2: Result of determination of the oxygenation index (arterialoxygen partial pressure/fraction of inspired oxygen [PaO₂/FiO₂])measured in the model of bleomycin-induced pulmonary fibrosis inrabbits. Whereas systemic PGI (6 ng/kg body weight/min] (PGI,prostacyclin) reduces the oxygenation index by 60% compared with thecontrol (190), the oxygenation index was markedly raised by inhaled NO[20 ppm] by 28% and sildenafil (oral) [1 mg/kg body weight] by 31%.

FIG. 3: Result of determination of the low V/Q perfusion measured by theinert gas exchange method (MIGET) [Wagner et al. J Appl Physiol.1974;36:588-99] from 7 patients with chronic thromboembolism anddisplaying secondary PHT (pulmonary hypertension). Compared with thecontrol group (3.25%), the shunting was increased with PGI (i.v.) [6ng/kg bodyweight/min] to 19%, with NO (inhaled) [20 ppm] to 5.3% andwith sildenafil (oral) [50 mg] to 5.3%.

FIG. 4: Result of measurement of the arterial oxygen partial pressure(PaO₂) on 7 patients with chronic thromboembolism and displayingsecondary PHT (pulmonary hypertension). The arterial oxygen partialpressure was improved by NO (inhaled) [20 ppm] and sildenafil (oral) [50mg] by respectively 1.8% and 7.6%, whereas the oxygen saturation fell by13% after administration of PGI (intravenous). In the same experiment,the vascular resistance was measured and determined as delta PVR by aright cardiac catheterization. The vascular resistance was reducedrespectively by 25%, 19% and 21% after administration of PGI(intravenous) [6 ng/kg bodyweight/min], NO (inhaled) [20 ppm] andsildenafil (oral) [50 mg].

FIG. 5: Result of determination of the shunting on 7 patients with ILD(interstitial lung disease) displaying secondary PHT. The measurementtook place by the inert gas exchange method (MIGET) [Wagner et al. JAppl Physiol. 1974;36:588-99]. The shunting was reduced to 5% and 4.8%,respectively, by NO (inhaled) [20 ppm] and sildenafil (oral) [50 mg].The shunting was increased to 18% after administration of PGI(prostacyclin, intravenous) 16 ng/kg bodyweight/min].

FIG. 6: Result of determination of the arterial oxygen partial pressure(PaO₂) on 7 patients with ILD displaying secondary PHT (pulmonaryhypertension) measured as delta PaO2. Whereas the arterial oxygenpartial pressure was increased by 4.8% and 13%, respectively, by NO(inhaled) [20 ppm] and sildenafil (oral) [50 mg], the oxygen saturationwas reduced by 12.5% in patients after administration of PGI(prostacyclin, intravenous) [6 ng/kg bodyweight/min].

FIG. 7: Result of the 6-minutes walking test measured on 4 patients withCOPD (chronic obstructive pulmonary disease). The change in the6-minutes walking distance on administration of 75 mg of sildenafil(oral) each day for a period of 6 months revealed an improvementrespectively of 41%, 45%, 74% and 150% for the 4 patients compared withthe starting point before treatment with sildenafil (0 months).

FIG. 8: Result of determination of the arterial oxygen saturation on 4patients with COPD (chronic obstructive pulmonary disease) treated withsildenafil (75 mg/day) (oral) measured at rest over a period of 6months. The arterial oxygen saturation in the patient improvedrespectively by 2%, 4%, 5% and 6%, compared with the saturation at thestart of the series of measurements (time: 0 months).

EXAMPLES

It was surprisingly found in experiments on the isolated perfused lungsthat there is oxygen- and ventilation-dependent synthesis of NO in thelung. It was shown in experimental pulmonary fibrosis on whole animals,in patients with chronic persistent thromboembolism and in patients withinterstitial lung disease that the vascular resistance decreases and, atthe same time, the O₂ saturation is improved on use of the selectivePDE5 inhibitor sildenafil (in contrast to PGI₂).

The effect of selective PDE5-inhibiting substances is confined to thearea of NO synthesis. A selective PDE5 inhibitor thus achieves itsselective vasodilating effect which differs from PGI (“intrapulmonaryselectivity ) through enhancing the local NO effect.

The hypothesis that PDE5 inhibitors, in contrast to other vasodilators,improve matching and, correspondingly, increase the O₂ saturation, andthus act as rematching drug, is proved experimentally and clinically bythe following results of studies on an animal model and on patients withinterstitial lung diseases.

Example 1 Isolated Perfused Lung

The isolated, ventilated rabbit lung with bloodless perfusion is anestablished organ model. Removal of the lung from the integrated organsystem makes It possible for the experimental situation to be free ofhumoral, central and metabolic influences from the body forinvestigating the complete, isolated, but intact organ. The ex vivoexperimental mode used permits continuous recording of measurements ofbiophysical parameters such as the pulmonary arterial pressure, theventilation pressure and the lung weight. Modification of the basicdesign additionally made alveolar deposition of substances possiblethrough nebulization in the present study.

New Zealand White crossbred rabbits of both sexes weighing between 2.6and 2.8 kg were used to carry out this series of experiments. A marginalear vein was punctured for injection of the necessary substances. Theanimals were then sedated with a mixture of ketamine (Ketanest®) andxylazine (Rompun®) (2/3 ratio of amounts) without suppressingspontaneous breathing and anticoagulated with 1 000 I.U. of heparin perkg/bodyweight. To eliminate sensitivity for the subsequent tracheotomy,a weal was raised in the skin with 10 ml of 0.2% Xylocaine®. The tracheawas exposed by careful layered dissection and could then be intubatedwith a metal cannula through a tracheotomy. Positive pressureventilation with ambient air was then carried out by the attachedventilation pump with a tidal volume of 30 ml, a respiratory rate of30/min and an end-expiratory pressure of 0 cm H₂O. Following the startof mechanical ventilation, anaesthesia was made more profound withKetanest®/Rompun® until analgesia and relaxation were complete.

After dissection of the aorta and the pulmonary artery, about 4% CO₂ wasadded to the ventilation with ambient air. Immediately after this, anincision was performed at the level of the outflow tract of the rightventricle, and the catheter (internal diameter 3 mm) filled with 3-4° C.cooled perfusion medium was introduced into the pulmonary artery.Perfusion was started with 1 0 mlymin. To avoid pressure stress on thepulmonary circulation, immediately thereafter the apex of the heart wasopened. The heart-lung specimen was removed after mobilization of thetrachea from the posterior wall of the thorax. Finally, the oesophagusand inferior vena cava and remaining strands of connective tissue weresevered. To complete the artificial circulation, a catheter wasintroduced into the left ventricle and fixed by an intramuralpurse-string suture. The left auricular appendage was, as a possibleinterfering fluid reservoir, ligated near to the ventricle wall. Thedissection was all carried out in a period not exceeding 30 minutes withcontinuous ventilation and perfusion. The lung was perfused withpulsatile flow from a peristaltic tubing pump. Inflow took place throughthe catheter which had already been introduced and fixed in thepulmonary artery during dissection. After passing through the pulmonarycirculation, venous outflow of the perfusion medium was possible throughthe tube fixed in the left ventricle. The perfusate flowing out wasreturned to the reservoir via a ladder-like cascade system. This cascadesystem made it possible to vary the hydrostatic pressure on thepulmonary vascular system between 0 and 10 cm H₂O (reference point wasthe hilum of the lung) by closing individual rungs (venous pressurechallenge).

The heart-lung package was suspended freely on an electronic weighingcell in a gas tight equilibration vessel for continuous recording of theweight. The perfusate containers consisted of double-walled glass;temperature-control fluid flowed through them from a thermal pump, whichmade it possible to control the temperature of the perfusate vessels andthus to control the temperature of the perfusate. It is possible tochange from ambient air ventilation to hypoxic respiratory gas (FiO₂0.03) by means of a selector switch. Simultaneously, the NO release aremeasured in the exhaled air and in the circulating perfusate. Theinfluence of alveolar distension on NO synthesis and release is found bychanging the ventilation pressures (in particular inspiratory pressureand end-expiratory pressure) (PEEP)).

The NO release is influenced by the distension of the alveoli and thusserves as a mediator of ventilation and distension of the alveoli.Consequently, NO synthesis in the lung is controlled by the twoparameters of O₂ content and alveolar ventilation. Hypoxia reduces NOsynthesis and there is a “stretch-induced” increase in NO release due toalveolar distension. These two mechanisms guarantee, in view of theinhomogeneous ventilation distribution of the lung under normalconditions, that perfusion takes place only where ventilation is good atthe same time (“normoxic ventilation”). The increased NO concentrationincreases the guanylate cyclase activity in the smooth muscle cells ofthe vessel wall, and smooth muscle cells are relaxed by the resultingCGMP. The vessel cross section (Q) and ventilation (V) are thus directlycoupled via NO synthesis and guarantee an optimal V/Q quotients(matching).

Example 2 Effect of Sildenafil on Bleomycin-induced Pulmonary Fibrosis

Healthy rabbits of both sexes were pretreated orally with a gyraseinhibitor (Baytril®) for one week. Ten animals pretreated in this waywere not treated with bleomyin and served as control, and, on the day ofexposure, the others were anaesthetized with a Ketanest®/Rompun®mixture, intubated intratracheally and ventilated mechanically. Anultrasonic nebulizer (MMAD 2.5 μm) was used to administer by inhalationexactly 1.8 U/kg of bodyweight of bleomycin under volume-controlledventilation. After 4, 8, 16, 24, 32 and 64 days (in each case n≧5) postexposure, the animals were again anaesthetized, provided with anarterial access (right carotid artery) and underwent bodyweight-adaptedventilation via a tracheostomy in a volume-controlled method. Thearterial pO₂ and pCO₂, and the static compliance of the lung weremeasured (by recording the intrathoracic pressure and with slowinflation/deflation manoeuvres). Subsequently, the lungs of theseanimals were dissected and perfused with a Krebs Hensefeit buffer. Underthese conditions, the capillary filtraton coefficient (cfc) was thenfound from the weight gain of the organ after increasing the pulmonaryvenous pressure by 7.5 mmHg, and the peak ventilation pressure wasfound. After completion of these measurements, the left main bronchuswas ligated in the end-inspiratory position and a bronchoalveolar lavage(BAL) was performed on the right lung. Subsequently, the large vesselsand airways of the right lung were dissected off and the organ washomogenized. The left lung was perfusion-fixed with 4% formalin solutionwhile maintaining a pressure gradient of 25 cm H₂O and was then storedin 4% formalin until embedded. Firstly, the cells were removed from theBAL, counted and differentiated via a Papenheim stain. The cell-free BALsupernatant was then aliquoted and submitted to further analysis of thesurfactant and coagulation properties and a determination of the matrixmetallo proteinases (MMPs) and their inhibitors (TIMPs) and of solublecollagen. Bronchoalveolar deposition of 1.8 U/kg of bodyweight ofbleomycin led initially to development of an ARDS-like event, with amassive restriction of gas exchange (paO₂/FiO₂ of >500 mmHg in thecontrols reduced to ˜110 mmHg on day 4), ground-glass opacities over allsections of the lung in the HRCT and an increase of about 5-fold in thecapillary filtration coefficient (cfc). In the later phase ofbleomycin-induced lung damage there was then development of pronouncedfibrosis which could be confirmed on the basis of the increase insoluble collagen in the BAL and the hydroxyproline in the tissue, on thebasis of the histological specimens and of the HRCT findings. Thus, theconcentration of soluble collagen in the BAL increased from 1.1±0.4μg/ml in the controls to a maximum of 38.3±12.5 μg/ml on day 16 afterbleomycin administration and was still distinctly increased even after64 days, at 7.0±2.2 μg/ml. The hydroxyproline content of the tissue wasapproximately doubled from day 16 onwards and showed a negligiblereduction subsequently. 32 days after exposure, the HRCT revealed apronounced reticular and homogeneous marking pattern of the lungs.Consistent with this, a pronounced increase in the extracellular matrixand an alveolar and also interstitial ingress of fibroblasts wasobservable in the histological sections. Besides the homogeneouslydistributed zones of fibrosis there were also thin hyperdistendedsections of lung with a honeycomb appearance.

As depicted in FIG. 1, measurements using the inert gas exchange methodrevealed that shunting was increased by 15% compared with the untreatedcontrol in the model of bleomycin-induced pulmonary fibrosis.Systemically administered PGI (vasodilatator) increased the shunting toabout 30%. Exogenous inhaled NO by contrast reduced the shunting. ThePDE5 inhibitor sidenafil given orally reduced the shunting even morethan NO. The data for O2 saturation (FIG. 2) correspond directly.Whereas systemic PGI reduced O₂ saturation, there were marked increasesin O₂ saturation with inhaled NO and sildenafil (oral).

Consequently, systemically administered vasodilators do not showintrapulmonary selectivity and enhance perfusion even where there islittle or absolutely no ventilation. By contrast, vasodilatorsadministered by inhalation dilate only where there is ventilation andthus show “intrapulmonary selectvity”—the shunting is reduced. PDE5inhibitors are administered orally and surprisingly show “intrapulmonaryselectivity”. Sildenafil differs from the normal vasodilator in reducingshunting.

Example 3 Sildenafil in Patients with Chronic Thromboembolism

7 patients with CTEPH underwent a Swan-Ganz catheter investigation withmeasurement of the ventilation/perfusion (V/Q) distribution (using themultiple inert gas elimination technique (MIGET)). After determinationof the baseline parameters (haemodynamics and gas exchange), all thepatients initially inhaled 20 ppm NO, followed by a second baselineperiod (10-15 min), and then PGI was infused (6 ng/kg bodyweight/min),again followed by a second baseline period (10-15 min) and then an oraldose of 50 mg of sildenafil was given (120-150 min follow-up). 3 of the7 patients were controlled by continuous nasal oxygen therapy in orderto reach an arterial oxygenation of >88%. The following parameters weremeasured under baseline conditions: mean pulmonary arterial pressure(mPAP) 52.1 +/−3.3 mmHg, cardiac index (CI) 2.2+/−0.1 |* min⁻¹*m⁻²,pulmonary vascular resistance index (PVRI) 1703.8+/−129.5 dyn*s*cm⁻⁶*m²,arterial pO2 72.5+/−3.3 mmHg and mixed venous oxygen saturation (SvO₂)of 63.4+/−2.2%. MIGET demonstrated a V/Q distribution disturbance in themiddle V/Q areas (broad distribution of perfusions), a low blood flowthrough shunt areas ((2.30+/−0.75%) and regions with poor ventilation(low V/Q areas, 3.25+/−1.84%), and a large dead-space ventilation.Administration of NO, PGI and sildenafil led in each case to a markedreduction in the pulmonary vascular resistance. Whereas NO andsildenafil left the ventilation/perfusion distribution virtuallyunchanged, on PGI infusion there was a considerable increase in thelow-V/Q perfusion (to 19%), resulting in a decrease in the arterialoxygen partial pressure during PGI infusion by 13% compared with thecontrol investigation. The perfusion of normally distributed V/Q areasremained virtually unchanged.

Secondary pulmonary hypertension, which is typical of these patients,was treated with PGI (intravenous), NO (inhaled) and with sildenafil(oral). The results on 7 patients show that perfusion of low-V/Q areas(V/Q<1) was increased slightly by NO (inhaled) but was greatly increasedby PGI (intravenous). Sildenafil (oral) had the same effect as NO(inhaled) (FIG. 3). The arterial oxygen partial pressure was not changedby NO (inhaled), was reduced by 13% by PGI (intravenous) and increasedwith sildenafil (oral) (FIG. 4). The vascular resistance in the lungs(PVR) was, by contrast, reduced equally by 20-25% under the threeconditions.

Consequently, it has been shown on patients with secondary pulmonaryhypertension that all three vasodilators reduce pulmonary hypertensionequally. Surprisingly, the influence of the vasodilators used onshunting varied widely. It was markedly increased by the systemicvasodilator PGI, whereas inhaled NO and the PDE5 inhibitor negligiblyaggrevated the matching. The use of sildenafil and NO resulted in eachcase in a selective improvement in the pharmacological oxygenation, thevalue determined for sildenafil being improved by comparison with NO.

Example 4 Effects of Sildenafil on Patients with ILD (Interstitial LungDisease)

7 patients with ILD underwent a Swan-Ganz catheter investigation withmeasurement of the ventilation/perfusion (V/Q) distribution (using themultiple inert gas elimination technique (MIGET)). After determinationof the baseline parameters (haemodynamics and gas exchange), all thepatients initially inhaled 20 ppm NO, followed by a second baselineperiod (10-15 min), and then PGI was infused (6 ng/kg bodyweight/min),again followed by a second baseline period (10-15 min) and then an oraldose of 50 mg of sildenafil was given (120-150 min follow-up). 5 of the7 patients were controlled by continuous nasal oxygen therapy in orderto reach an arterial oxygenation of >88%. The following parameters weremeasured under baseline conditions: mean pulmonary arterial pressure(mPAP) 39.6+/−2.8 mmHg and pulmonary vascular resistance index (PVRI)1255+/−215 dyn*s*cm−5*m². MIGET demonstrated a blood flow through shuntareas (7.2+/−1.8%) and a large dead-space ventilation. Administration ofNO, PGI and sildenafil led in each case to a marked reduction in thepulmonary vascular resistance. Whereas NO and sildenafil left theventilation/perfusion distribution virtually unchanged on PGI infusionthere was a considerable increase in the shunt perfusion (to 18%),resulting in a decrease in the arterial oxygen partial pressure duringPGI infusion by 12.5% compared with the control investigation. Theperfusion of normally distributed V/Q areas remained virtuallyunchanged.

Patients with ILD displayed secondary pulmonary hypertension and weretreated with vasodilators for this. The results on 7 patients show thatNO (inhaled) and sildenafil (oral) had no effect on the markedlyincreased shunting in these patients. By contrast, PGI (intravenous)increased the lung areas from 7% to almost 20% and thus caused adeterioration in matching (FIG. 5). Corresponding to the matching, PGIreduced the O₂ saturation by 12%, whereas NO brought about animprovement of 5% and sildenafil one of 15% (FIG. 6). The secondarypulmonary vascular resistance (PVR) was distinctly reduced by about 25%with all three medications (FIG. 6).

Improvements in the 6-min walking [Wijkstra et al., Thorax 1994,49(5):468-72] (FIG. 7) and the corresponding measurements of thearterial O₂ saturation (FIG. 8) were followed on 4 patients during 6months with 50 mg/d sildenafil (oral). The data show a markedimprovement in the functional capacity of the investigated patientsafter administration of sildenafil over this time.

1. Use of PDE5 inhibitors for producing medicaments for the treatment ofpartial and global respiratory failure.
 2. Use of PDE5 inhibitors in thetreatment of partial and global respiratory failure.
 3. Use of selectivePDE5 inhibitors for producing medicaments for the treatment ofrespiratory failure in patients showing a mismatch of pulmonaryventilation and pulmonary perfusion.
 4. Use according to claim 3,characterized in that patients with an exercise-dependent mismatch aretreated.
 5. Use of selective PDE5 inhibitors according to claim 3,characterized in that patients with an age-related mismatch are treated.6. Use of selective PDE5 inhibitors according to claim 3, characterizedin that patients with a pathologically caused mismatch are treated. 7.Use of selective PDE5 inhibitors according to any of claims 3 to 6,characterized in that patients with a mismatch of V/Q<0.1 are treated.8. Use of selective PDE5 inhibitors according to claim 3, characterizedin that COPD patients with a predominant bronchitic component aretreated.
 9. Use of selective PDE5 inhibitors according to claim 8,characterized in that COPD patients with a V/Q<0.1 are treated.
 10. Useof selective PDE5 inhibitors according to claim 3, characterized in thatCOPD patients with an emphysematous component are treated.
 11. Use ofselective PDE5 inhibitors according to claim 10, characterized in thatCOPD patients with a V/Q>10 are treated.
 12. Use of selective PDE5inhibitors according to claim 3, characterized in that patients withorthopnoea are treated.
 13. Use of selective PDE5 inhibitors accordingto claim 3, characterized in that patients with sleep apnoea aretreated.
 14. Use of selective PDE5 inhibitors according to claim 3,characterized in that the mismatch is therapy-induced.
 15. Use ofselective PDE5 inhibitors according to claim 14, characterized in thatthe mismatch is caused by administration of nonselectively vasodilatingmedicaments.
 16. Use of selective PDE5 inhibitors according to claim 15,characterized in that a nonselectively vasodilating medicament is anonselectively vasodilating antiobstructive agent.
 17. Use of selectivePDE5 inhibitors according to claim 16, characterized in that anonselectively vasodilating antiobstructive agent is selected from thegroup consisting of endothelin antagonist, Ca channel blocker, ACEinhibitor, ATII antagonist and β blocker.
 18. Use of PDE5 inhibitors forproducing medicaments for the treatment of patients with musculardysfunction caused by perfusion/demand mismatch.
 19. Use according toany of claims 1 to 18, characterized in that the PDE5 inhibitor or theselective PDE5 inhibitor is an active ingredient which is selected fromthe group consisting of3-ethyl-8-[2-(4-morpholinylmethyl)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione,1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide,9-bromo-2-(3-hydroxypropoxy)-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-[k]-carbazol-4-one,4-(1,3-benzodioxol-5-ylmethylamino)-2-(1-imidazolyl)-6-methylthieno[2,3-pyrimidine,6-(2-isopropyl-4,5,6,7-terahydropyrazolo[1,5-a]pyridin-3-yl)-5-methyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one,5-(4-methylbenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-pyridin-4-ylmethyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(4-bromobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-benzyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(3,4-dimethoxybenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one,5-(3,4-dichlorobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-biphenyl-4-ylmethyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(4-aminobenzyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(hydroxyphenylmethyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one,5-benzo[1,3]dioxol-5-ylmethyl-3-[1-methyl-4-phenylbutyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,N-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo-[4,5-d]pyrimidin-5-ylmethyl]phenylacetamide,5-benzoyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]-pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-[4-(morpholine-4-sulphinyl)benzyl]-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-[3-(morpholine-4-sulphonyl)benzyl]-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one,N-methyl-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]-benzenesulphonamide,N-(2-dimethylaminoethyl)-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonamide,N-(2-hydroxyethyl)-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonamide,ethyl1-[3-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonyl]piperidinecarboxylate,3(1-methyl-4-phenylbutyl)-5-[4-(4-methylpiperazin-1-sulphonyl)benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5d]pyrimidin-7-one,5-benzo[1,3]dioxol-5-ylmethyl-3-[1-ethyl-heptyl]-3,6-dihydro-[1,2,3]-triazolo[4,5-d]pyrimidin-7-one,3-[1-(1-hydroxyethyl)-4-phenylbutyl]-5-[4-(morpholine-4-sulphonyl)benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-[6-fluoro-1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol,1-benzyl-6-fluoro-3-[5-(hydroxymethyl)furan-2-yl]-1H-indazole,2-(1H-imidazol-1-yl)-6-methoxy-4-(2-methoxyethylamino)quinazoline,1-[[3-dihydro-8-oxo-1H-imidazo[4,5-g]quinazolin-6-yl)-4-propoxyphenyl]sulphonyl]-4-methylpiperazine,4-(3-chloro-4-methoxybenzylamino)-1-(4-hydroxypiperidin-1-yl)phthalazine-6-carbonitrile,1-[6-chloro-4-(3,4-methylendioxybenzylamino)quinazolin-2-yl]piperidin-4-carboxylicacid, (6R, 12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octa-hydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione(tadalafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione,4-ethoxy-2-phenylcycloheptylimidazole, (6-bromo-3-methoxymethylimidazo[1,2-a]pyrazin-8-yl)methylamine,8-[(phenylmethyl)thio]4-(1-morpholinyl)-2-(1-piperazinyl)pyrimidino[4,5-d]pyrimidine,(+)-cis-5-methyl-2-[4-(trifluoromethyl)benzyl]-3,4,5,6a,7,8,9-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one,cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5imidazo[2,1-b]purin-4-one,5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(slidenafil),1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine,2-(2-propoxyphenyl)purin-6(1H)-one,2-(2-propoxyphenyl)-1,7-dihydro-5H-purin-6-one, methyl2-(2-methylpyridin-4-ylmethyl)-1-oxo-8-(2-pyrimidinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-[2,7]naphthyridin-3-carboxylate,methyl 2-(4-aminophenyl)-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydroisoquinoline-3-carboxylate,2-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)phenyl]-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(vardenafil),3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2-(1H)-quinolinone(vesnarinone), 1-cyclopentyl-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one,1-cyclopentyl-6-(3-ethoxy-4-pyridinyl)-3-ethyl-1,7-dihydro-4H-pyrazolo[3,4-d]-pyrimidin-4-one,6-o-propoxyphenyl-8-azapurin-6-one,3,6-dihydro-5-(o-propoxyphenyl)-7H-v-triazolo[4,5-d]pyrimidin-7-one and4-methyl-5-(4-pyridinyl)thiazole-2-carboxamide and the pharmacologicallyacceptable salts of these compounds.
 20. Use according to any of claims1 to 18, characterized in that the PDE5 inhibitor or the selective PDE5inhibitor is an active ingredient selected from the group consisting oftadalafil, sildenafil, vardenafil and vesnarinone and thepharmacologically acceptable salts of these compounds. 21.Pharmaceutical preparation comprising at least one selective PDE5inhibitor and at least one nonselectively vasodilating antiobstructiveagent.
 22. Pharmaceutical preparation according to claim 21 for thetreatment of partial and global respiratory failure.
 23. Pharmaceuticalpreparation according to claim 21 for the treatment of disordersselected from the group consisting of COPD, bronchial asthma, latentpulmonary hypertension, emphysema, combined ventilation disturbances andchronic left heart failure with pulmonary congestion.
 24. Pharmaceuticalpreparation according to any of claims 21 to 23, characterized in thatthe selective PDE5 inhibitor is an active ingredient selected from thegroup consisting of3-ethyl-8-[2-(4-morpholinylmethyl)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione,1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide,9-bromo-2-(3-hydroxypropoxy)-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-[k]-carbazol-4-one,4-(1,3-benzodioxol-5-ylmethylamino)-2-(1-imidazolyl)-6-methylthieno[2,3-pyrimidine,6-(2-isopropyl-4,5,6,7-terahydropyrazolo[1,5-a]pyridin-3-yl)-5-methyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one,5-(4-methylbenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-pyridin-4-ylmethyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(4-bromobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-benzyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(3,4-dimethoxybenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one,5-(3,4-dichlorobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-biphenyl-4-ylmethyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(4-aminobenzyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(hydroxyphenylmethyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one,5-benzo[1,3]dioxol-5-ylmethyl-3-[1-methyl-4-phenylbutyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,N-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo-[4,5-d]pyrimidin-5-ylmethyl]phenylacetamide,5-benzoyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]-pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-[4-(morpholine-4-sulphinyl)benzyl]-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-[3-(morpholine-4-sulphonyl)benzyl]-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one,N-methyl-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]-benzenesulphonamide,N-(2-dimethylaminoethyl)-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonamide,N-(2-hydroxyethyl)-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonamide,ethyl1-[3-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonyl]piperidinecarboxylate,3(1-methyl-4-phenylbutyl)-5-[4-(4-methylpiperazin-1-sulphonyl)benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5d]pyrimidin-7-one,5-benzo[1,3]dioxol-5-ylmethyl-3-[1-ethyl-heptyl]-3,6-dihydro-[1,2,3]-triazolo[4,5-d]pyrimidin-7-one,3-[1-(1-hydroxyethyl)-4-phenylbutyl]-5-[4-(morpholine-4-sulphonyl)benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-[6-fluoro-1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol,1-benzyl-6-fluoro-3-[5-(hydroxymethyl)furan-2-yl]-1H-indazole,2-(1H-imidazol-1-yl)-6-methoxy-4-(2-methoxyethylamino)quinazoline,1-[[3-dihydro-8-oxo-1H-imidazo[4,5-g]quinazolin-6-yl)-4-propoxyphenyl]sulphonyl]-4-methylpiperazine,4-(3-chloro-4-methoxybenzylamino)-1-(4-hydroxypiperidin-1-yl)phthalazine-6-carbonitrile,1-[6-chloro-4-(3,4-methylendioxybenzylamino)quinazolin-2-yl]piperidin-4-carboxylicacid, (6R, 12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octa-hydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione(tadalafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione,4-ethoxy-2-phenylcycloheptylimidazole, (6-bromo-3-methoxymethylimidazo[1,2-a]pyrazin-8-yl)methylamine,8-[(phenylmethyl)thio]4-(1-morpholinyl)-2-(1-piperazinyl)pyrimidino[4,5-d]pyrimidine,(+)-cis-5-methyl-2-[4-(trifluoromethyl)benzyl]-3,4,5,6a,7,8,9-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one,cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5imidazo[2,1-b]purin-4-one,5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(slidenafil),1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine,2-(2-propoxyphenyl)purin-6(1H)-one,2-(2-propoxyphenyl)-1,7-dihydro-5H-purin-6-one, methyl2-(2-methylpyridin-4-ylmethyl)-1-oxo-8-(2-pyrimidinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-[2,7]naphthyridin-3-carboxylate,methyl 2-(4-aminophenyl)-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydroisoquinoline-3-carboxylate,2-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)phenyl]-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(vardenafil),3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2-(1H)-quinolinone(vesnarinone), 1-cyclopentyl-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one,1-cyclopentyl-6-(3-ethoxy-4-pyridinyl)-3-ethyl-1,7-dihydro-4H-pyrazolo[3,4-d]-pyrimidin-4-one,6-o-propoxyphenyl-8-azapurin-6-one,3,6-dihydro-5-(o-propoxyphenyl)-7H-v-triazolo[4,5-d]pyrimidin-7-one and4-methyl-5-(4-pyridinyl)thiazole-2-carboxamide and the pharmacologicallyacceptable salts of these compounds.
 25. Pharmaceutical preparationaccording to any of claims 21 to 23, characterized in that the selectivePDE5 inhibitor is an active ingredient selected from the groupconsisting of tadalafil, sildenafil, vardenafil and vesnarinone and thepharmacologically acceptable salts of these compounds.
 26. Commercialproduct consisting of a conventional secondary packaging, of a primarypackaging containing the medicament and, if desired, of a packageinsert, where the medicament is used for the treatment of partial andglobal respiratory failure, the suitability of the medicament for thetreatment of partial and global respiratory failure is indicated on thesecondary packaging and/or on the package insert of the commercialproduct, and the medicament comprises an active ingredient from theclass of PDE5 inhibitors.
 27. Ready-to-use medicament comprising a PDE5inhibitor and an indication that this medicament can be employed for thetreatment of partial and global respiratory failure.
 28. A method oftreating partial and global respiratory failure in a human in needthereof comprising the step of administering to said human atherapeutically effective amount of a PDE5 inhibitor.
 29. A method oftreating respiratory failure in a human showing a mismatch of pulmonaryventilation and pulmonary perfusion comprising the steps ofadministration to said human in need a therapeutically effective amountof a selective PDE5 inhibitor.
 30. The method according to claim 29,wherein the human in need has an exercise-dependent mismatch.
 31. Themethod according to claim 29, wherein the human in need has anage-related mismatch.
 32. The method according to claim 29, wherein thehuman in need has a pathologically caused mismatch.
 33. The methodaccording to claim 29 to 32, wherein the human in need has a mismatch ofV/Q<0.1.
 34. The method according to claim 29, wherein the human in needis a COPD patient with a predominant bronchitis component.
 35. Themethod according to claim 34, wherein the human in need is a COPDpatient with a V/Q<0.1.
 36. The method according to claim 29, whereinthe human in need is a COPD patient with an emphysematous component. 37.The method according to claim 36, wherein the human in need is a COPDpatient with a V/Q>10.
 38. A method according to claim 29, wherein thehuman in need has orthopnoea.
 39. A method according to claim 29,wherein the human in need has sleep apnoea.
 40. The method according toclaim 29, wherein the human in need has a therapy-induced mismatch. 41.The method according to claim 40, wherein the human in need has amismatch caused by administration of nonselectively vasodilatingmedicaments.
 42. The method according to claim 41, wherein thenonselectively vasodilating medicament is a nonselectively vasodilatingantiobstructive agent.
 43. The method according to claim 42, wherein thenonselectively vasodilating antiobstructive agent is selected from thegroup consisting of endothelin antagonist, Ca channel blocker, ACEinhibitor, ATII antagonist and β blocker.
 44. A method of treatingmuscular dysfunction in a human showing a perfusion/demand mismatchcomprising the step of administering to said human a therapeuticallyeffective amount of a PDE5 inhibitor.
 45. The method according to one ofthe claims 28 to 44, characterized in that the PDE5 inhibitor or theselective PDE5 inhibitor is an active ingredient which is selected fromthe group consisting of3-ethyl-8-[2-(4-morpholinylmethyl)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione,1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxamide,9-bromo-2-(3-hydroxypropoxy)-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-[k]-carbazol-4-one,4-(1,3-benzodioxol-5-ylmethylamino)-2-(1-imidazolyl)-6-methylthieno[2,3-pyrimidine,6-(2-isopropyl-4,5,6,7-terahydropyrazolo[1,5-a]pyridin-3-yl)-5-methyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one,5-(4-methylbenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-pyridin-4-ylmethyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(4-bromobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-benzyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(3,4-dimethoxybenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one,5-(3,4-dichlorobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-biphenyl-4-ylmethyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(4-aminobenzyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-(hydroxyphenylmethyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one,5-benzo[1,3]dioxol-5-ylmethyl-3-[1-methyl-4-phenylbutyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,N-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo-[4,5-d]pyrimidin-5-ylmethyl]phenylacetamide,5-benzoyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]-pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-[4-(morpholine-4-sulphinyl)benzyl]-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one,3-(1-methyl-4-phenylbutyl)-5-[3-(morpholine-4-sulphonyl)benzyl]-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one,N-methyl-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]-benzenesulphonamide,N-(2-dimethylaminoethyl)-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonamide,N-(2-hydroxyethyl)-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonamide,ethyl1-[3-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonyl]piperidinecarboxylate,3(1-methyl-4-phenylbutyl)-5-[4-(4-methylpiperazin-1-sulphonyl)benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5d]pyrimidin-7-one,5-benzo[1,3]dioxol-5-ylmethyl-3-[1-ethyl-heptyl]-3,6-dihydro-[1,2,3]-triazolo[4,5-d]pyrimidin-7-one,3-[1-(1-hydroxyethyl)-4-phenylbutyl]-5-[4-(morpholine-4-sulphonyl)benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one,5-[6-fluoro-1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol,1-benzyl-6-fluoro-3-[5-(hydroxymethyl)furan-2-yl]-1H-indazole,2-(1H-imidazol-1-yl)-6-methoxy-4-(2-methoxyethylamino)quinazoline,1-[[3-dihydro-8-oxo-1H-imidazo[4,5-g]quinazolin-6-yl)-4-propoxyphenyl]sulphonyl]-4-methylpiperazine,4-(3-chloro-4-methoxybenzylamino)-1-(4-hydroxypiperidin-1-yl)phthalazine-6-carbonitrile,1-[6-chloro-4-(3,4-methylendioxybenzylamino)quinazolin-2-yl]piperidin-4-carboxylicacid, (6R, 12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octa-hydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione(tadalafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione,4-ethoxy-2-phenylcycloheptylimidazole, (6-bromo-3-methoxymethylimidazo[1,2-a]pyrazin-8-yl)methylamine,8-[(phenylmethyl)thio]4-(1-morpholinyl)-2-(1-piperazinyl)pyrimidino[4,5-d]pyrimidine,(+)-cis-5-methyl-2-[4-(trifluoromethyl)benzyl]-3,4,5,6a,7,8,9-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one,cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5imidazo[2,1-b]purin-4-one,5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(slidenafil),1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine,2-(2-propoxyphenyl)purin-6(1H)-one,2-(2-propoxyphenyl)-1,7-dihydro-5H-purin-6-one, methyl2-(2-methylpyridin-4-ylmethyl)-1-oxo-8-(2-pyrimidinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-[2,7]naphthyridin-3-carboxylate,methyl 2-(4-aminophenyl)-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydroisoquinoline-3-carboxylate,2-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)phenyl]-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(vardenafil),3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2-(1H)-quinolinone(vesnarinone), 1-cyclopentyl-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one,1-cyclopentyl-6-(3-ethoxy-4-pyridinyl)-3-ethyl-1,7-dihydro-4H-pyrazolo[3,4-d]-pyrimidin-4-one,6-o-propoxyphenyl-8-azapurin-6-one,3,6-dihydro-5-(o-propoxyphenyl)-7H-v-triazolo[4,5-d]pyrimidin-7-one and4-methyl-5-(4-pyridinyl)thiazole-2-carboxamide and the pharmacologicallyacceptable salts of these compounds.
 46. The method according to one ofthe claims 28 to 44, characterized in that the PDE5 inhibitor or theselective PDE5 inhibitor is an active ingredient selected from the groupconsisting of tadalafil, sildenafil, vardenafil and vesnarinone and thepharmacologically acceptable salts of these compounds.